Lyme disease is an important health concern and the leading arthropod-borne disease in N. America and Europe. In the U.S. in 2003, approximately 22,000 cases were reported to the CDC. Lyme disease is caused by the zoonotic pathogens Borrelia burgdorferi, B. garinii and B. afzelii which are transmitted to humans through the bite of infected Ixodid ticks. The first Lyme disease vaccine licensed for use in humans entered the market in 1998 but was removed from the market in 2002. There is a pressing need to carefully characterize new potential vaccinogens and move forward with vaccine development. Efforts to develop a new generation of vaccines have been hampered by the antigenic and genetic complexity of the Lyme disease spirochetes and our general lack of knowledge regarding the antigenic structure of Borrelia surface proteins. Outer surface protein C (OspC) has emerged as a potential candidate for vaccine development. OspC is a 22 kDa lipoprotein that is expressed during early infection and is highly antigenic. Recent analyses indicate that it plays an important role in the pathogenesis of Lyme disease. In spite of the potential importance of OspC in Borrelia pathogenesis and its well documented protective capabilities, a significant void remains in our understanding of the Ab response to this protein and its antigenic structure. One of the difficulties that has been encountered in developing OspC as a vaccinogen is its extensive genetic and antigenic variability. OspC sequences form approximately 21 distinct phyletic groups that are referred to as OspC types (differentiated by letter designations). Only a subset of OspC types are associated with invasive infection in humans. The determination of OspC crystal structures has identified specific domains that are likely to be surface exposed and presented by the Lyme spirochetes during natural infection. Hence, we now have the tools and resources facilitate the rational design and construction of an effective vaccine. In this application, we present evidence that specific epitopes within OspC are immunodominant during infection, bactericidal and are major linear determinants in the OspC type specific Ab response. In aim 1we will identify the immunodominant epitopes of each OspC type and determine if each elicits a bactericidal Ab response. In aim 2 we will construct a polyvalent chimeric vaccinogen and in aim 3 we will assess its efficacy.